RNA-Dependent Protein Kinase Is Essential for 2-Methoxyestradiol-Induced Autophagy in Osteosarcoma Cells

Caihong Yang, Kristen L. Shogren, Ribu Goyal, Dalibel Bravo, Michael J Yaszemski, Avudaiappan Maran

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Osteosarcoma is the most common primary malignant bone tumor in children and young adults. Surgical resection and adjunctive chemotherapy are the only widely available options of treatment for this disease. Anti-tumor compound 2-Methoxyestradiol (2-ME) triggers cell death through the induction of apoptosis in osteosarcoma cells, but not in normal osteoblasts. In this report, we have investigated whether autophagy plays a role in 2-ME actions on osteosarcoma cells. Transmission electron microscopy imaging shows that 2-ME treatment leads to the accumulation of autophagosomes in human osteosarcoma cells. 2-ME induces the conversion of the microtubule-associated protein LC3-I to LC3-II, a biochemical marker of autophagy that is correlated with the formation of autophagosomes. Conversion to LC3-II is accompanied by protein degradation in 2-ME-treated cells. 2-ME does not induce autophagosome formation in normal primary human osteoblasts. In addition, 2-ME-dependent autophagosome formation in osteosarcoma cells requires ATG7 expression. Furthermore, 2-ME does not induce accumulation of autophagosomes in osteosarcoma cells that express dominant negative mutant RNA-dependent protein kinase (PKR) and are resistant to anti-proliferative and anti-tumor effects of 2-ME. Taken together, our study shows that 2-ME treatment induces PKR-dependent autophagy in osteosarcoma cells, and that autophagy could play an important role in 2-ME-mediated anti-tumor actions and in the control of osteosarcoma.

Original languageEnglish (US)
Article numbere59406
JournalPLoS One
Volume8
Issue number3
DOIs
StatePublished - Mar 19 2013

Fingerprint

eIF-2 Kinase
osteosarcoma
autophagy
Autophagy
Osteosarcoma
protein kinases
RNA
cells
Tumors
neoplasms
osteoblasts
Osteoblasts
Neoplasms
2-methoxyestradiol
resection
protein degradation
young adults
microtubules
drug therapy
transmission electron microscopy

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

RNA-Dependent Protein Kinase Is Essential for 2-Methoxyestradiol-Induced Autophagy in Osteosarcoma Cells. / Yang, Caihong; Shogren, Kristen L.; Goyal, Ribu; Bravo, Dalibel; Yaszemski, Michael J; Maran, Avudaiappan.

In: PLoS One, Vol. 8, No. 3, e59406, 19.03.2013.

Research output: Contribution to journalArticle

Yang, Caihong ; Shogren, Kristen L. ; Goyal, Ribu ; Bravo, Dalibel ; Yaszemski, Michael J ; Maran, Avudaiappan. / RNA-Dependent Protein Kinase Is Essential for 2-Methoxyestradiol-Induced Autophagy in Osteosarcoma Cells. In: PLoS One. 2013 ; Vol. 8, No. 3.
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